The progression of normal cells to cancer cells can be influenced by a variety of factors, including changes in the immune system, hormonal status, gene expression and signalling between tissues. A particularly important factor in cancer progression is somatic mutation, which plays a role in cancers of most, if not all, tissue types.
The accumulation of somatic mutations in various genes appears directly related to cancer progression. This has been demonstrated using various animal models in which an increase in somatic mutagenesis resulting from, for example, impaired DNA polymerase proofreading or DNA repair, was associated with accelerated tumor progression (see e.g. Venkatesan et al. (2007). Mol. Cell. Biol. 27: 7669-7682; and Albertson (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 17101-17104). Increased somatic mutagenesis of various genes has also been associated with a variety of cancers. For example, somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers. Somatic TP53 mutations occur in almost every type of cancer at rates from 38%-50% in ovarian, esophageal, colorectal, head and neck, larynx, and lung cancers to about 5% in primary leukemia, sarcoma, testicular cancer, malignant melanoma, and cervical cancer, and advanced stage or aggressive cancer subtypes (such as triple negative or HER2-amplified breast cancers) are associated with an increased frequency of somatic mutations in TP53 (reviewed in Olivier et al. (2010) Cold Spring Harb Perspect Biol 2:a001008). Other genes associated with cancer that accumulate somatic mutations include, for example, BRAF, HRAS, KRAS2 and NRAS, although over 25000 genes are now included in COSMIC, the online database of somatically acquired mutations found in human cancer.
Somatic mutagenesis can be caused by environmental factors, such as cigarette smoke, UV light and radiation, and/or biological factors or processes, such as chromosome translocation, DNA mis-repair or non-repair, and enzyme-initiated somatic hypermutation (SHM). Determining the cause and extent of somatic mutagenesis in cells can not only assist in diagnosing conditions associated with somatic mutagenesis or predicting the risk of developing such conditions, but can also assist in developing the most appropriate treatment or prevention protocols. Thus, there is a need for accurate methods for determining the presence of somatic mutagenesis and identifying which mutagenic agent or agents are responsible for somatic mutagenesis in a subject.